The long-range goals of this project are to identify CNS sites, neurotransmitter systems and receptors involved in mediating the actions of ethanol (E) and promoting high alcohol-seeking behavior. The overall hypothesis to be tested is that there are innate neurobiological differences within key CNS limbic structures which underlie genetic vulnerability to high alcohol drinking behavior. The objectives of this proposal are to determine (1) the effects of chronic alcohol consumption on neuronal activity within limbic and other important CNS structures; (2) the effects of E drinking conditions on altering neuronal activity within limbic and other important CNS structures; (3) the involvement of ventral tegmental area (VTA) dopamine (DA) neurons, and (5-HT) serotonin transmission and 5-HT3 receptors in alcohol-seeking behavior; and (4) differences between rat lines, selectively bred for disparate alcohol drinking behaviors, in GABAA and 5-HT3 receptor regulation of VTA mediated reinforcement processes. The overall hypothesis will be tested in the alcohol-preferring P, alcohol-nonpreferring NP, high alcohol-drinking HAD and low alcohol-drinking LAD lines. The [14C]-2-deoxyglucose (2-DG) uptake procedure coupled to quantitative autoradiography will be employed to assess changes in regional CNS neuronal activity of P and HAD rats that may be associated with chronic alcohol drinking and alcohol drinking conditions. In vivo microdialysis will be used to measure changes in extracellular levels of DA and 5-HT in the VTA and/or nucleus accumbens (ACB) to examine the effects of local E and 5-HT3 agonist administration, and alcohol drinking conditions on DA and 5-HT neuronal activity. The intracranial self-administration (ICSA) procedure will be utilized to examine line differences in reinforcement processes mediated by GABAA and 5-HT3 receptors within the VTA. The results of this project will provide fundamental information toward understanding the neurobiological mechanisms underlying high alcohol-seeking behavior. Such information would be important for developing pharmacotherapies.